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David Parker PhD

University Lecturer
Tel: +44 (0)1223 333836, Fax: +44 (0)1223 333840, E-mail: djp27@cam.ac.uk

Neuronal networks

In order to understand how normal behaviours are generated, and what happens when things go wrong, we need to understand how neurons interact in the networks that process sensory inputs, perform cognitive functions, and program motor outputs. Network activity reflects integrated molecular, cellular, and synaptic properties. We thus need to know the types of neurons in a network, their synaptic connections, and their functional properties. While these properties must generate reliable network outputs, they must also be plastic and allow the output to change as required. I am interested in examining how interactions in neuronal networks could influence behaviourally relevant network outputs.

Network analyses are complicated by the large number of components that have to be studied. Even in supposedly simple networks with a limited number of neurons and synapses, there can still be a huge range of functional components, components that may vary intrinsically within or between animals, and that are subject to activity, neuromodulator, or homeostatic plasticity changes. Understanding these networks in isolation can be difficult, and relating them to behaviourally-relevant outputs compounds these difficulties. These aspects have been the focus of a recent edition of the Philosophical Transactions of the Royal Society

I use the locomotor network in the spinal cord of the lamprey as a model vertebrate system to examine general principles of network function. This network generates a basic alternating output that coordinates muscle activity on the left and right sides of the body, and offers a relatively simple vertebrate system in which to address the cellular and synaptic mechanisms in an intact functional network. While the lamprey locomotor network is claimed to be "characterised", there are in reality many areas of uncertainty, even at the level of its basic organisation, that need to be addressed before any claims to understanding how this network generates motor outputs could reasonably (i.e. scientifically) be made or accepted. Consider the following network scheme (from Grillner and Jessell 2009 Curr Opin Neurobiol 19: 1-15).

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This scheme has been repeated in modified forms in many reviews associated with the significant claims that the network is characterised, and that behaviour can be explained in terms of interactions between identified nerve cells and their associated molecular, cellular, and synaptic properties. These claims are almost universally accepted and cited. In reality this network is at best hypothetical, and at worse knowingly wrong: neurons are included without their network relevance being established, others are removed for personal convenience, and approximately 50% of the synaptic connections, which are claimed in print to have been verified experimentally, lack any experimental evidence at all. The very significant extent to which these claims fail to match reality is outlined further in my Royal Society reviews from 2006 and 2010. In addition to the scientific questions this raises, that a network can be so widely accepted given the obvious logical flaws and major gaps in the necessary details (specifically the synaptic connectivity where claims of experimental evidence cannot be supported) raises issues related to the social aspects of science.

We combine electrophysiological, computational, molecular, and anatomical approaches to analyses of the network. In addition to addressing various uncertainties of the claimed network scheme, we examine the following specific aspects:

The activity-dependent plasticity of network synapses
Activity-dependent plasticity has been studied extensively. Most studies focus on long-term changes. We are examining the role of the short-term activity-dependent plasticity of specific types of network synapses that develops over repetitive cycles of network activity. We are not aiming to characterise the mechanisms of activity-dependent plasticity (although we do address these aspects), but instead to focus on how the specific forms of activity-dependent plasticity at different classes of network synapse interact to influence the patterning of ongoing network outputs. This is done using experimental and computational approaches (see Jia and Parker 2009).

Synaptic and network variability
Variability was traditionally ignored in the nervous system, variable responses between cells or synapses being considered as "noise" in the data. It is now largely recognised that variability is an intrinsic component of the nervous system (and in fact must be of any adaptive physiological system), and could influence cellular activity and synaptic integration and thus network function. We are examining how functional variability influences network outputs (which are themselves highly variable) and the associated variability of network synapses (see Parker 2003). While specific classes of cells and synapses can be identified on anatomical grounds (cell body location, axonal projections, or transmitter content), within these defined populations are sub-groups that can have markedly different functional properties. We aim to examine the relevance of these different sub-groups to network function.

The role of adaptive changes in the functional recovery of locomotor function after spinal cord injury
A major aspect of the work is currently to examine the network mechanisms that may underlie the recovery of function after spinal cord injury. As in other lower vertebrates, the lamprey recovers locomotor function after complete spinal cord lesions. While analyses of this recovery have focused for many years on the regrowth of axons across lesion sites, we are examining the role of changes in functional properties below lesion sites. We have identified morphological and functional changes in network neurons and sensory inputs below lesion sites (Cooke and Parker 2009; Hoffman and Parker 2011; Svensson et al 2013), and aim to try and relate these changes to improvements in locomotor performance.

Funding: None

Recent publications
Svensson E, Kim O, Parker D (2013) Altered GABA and somatostatin modulation of proprioceptive feedback after spinal cord injury in lamprey. Neuroscience 235: 109-118.

Parker D, Srivastava V (2013) Dynamic systems approaches and levels of analysis in the nervous system. Frontiers in Physiology 4: Article 15.

Cooke R, Luco S, Parker D (2012) Tonic manipulations of spinal cord excitability evoke developmentally-dependent compensatory changes in the lamprey spinal cord. J Comp Physiol 198: 25-41.

Hoffman N, Parker D (2011) Interactive and individual effects of sensory potentiation and region-specific changes in excitability after spinal cord injury. Neuroscience 199: 563-576.

Hoffman N, Parker D (2010) Lesioning alters functional properties in isolated spinal cord hemisegmental networks. Neuroscience 168: 732-743.

Parker D (2010) Neuronal network analyses: premises, promises and uncertainties. Phil Trans R Soc Lond B 365: 2315-2328.

Jia Y, Parker D (2009). Activity-dependent synaptic plasticity and the patterning of hemisegmental spinal cord network activity. 2009 3rd International Conference on Bioinformatics and Biomedical Engineering (iCBBE 2009): 1-4.

Cooke RM, Parker D (2009) Locomotor recovery after spinal cord lesions in the lamprey is associated with functional and ultrastructural changes below lesion sites. J Neurotrauma 26: 597-612.

Srivastava V, Parker D, Edwards SF (2008) The nervous system might 'orthogonalize' to discriminate. J Theor Biol 253: 514-517.

Baudoux S, Parker D (2008) Glial-toxin-mediated disruption of spinal cord locomotor network function and its modulation by 5-HT. Neuroscience 153: 1332-1343.

Bevan S, Vakharia V, Parker D (2008) Changes in gene expression and integrin-mediated structural changes are associated with long-term plasticity of a spinal cord locomotor network. Neuroscience 152: 160-168.

Parker D, Gilbey T (2007) Developmental differences in neuromodulation and synaptic properties in the lamprey spinal cord. Neuroscience 145: 142-152.

Parker D (2007) The role of activity-dependent synaptic plasticity and variability in the patterning of oscillatory network activity. Neuronal Network Research Horizons. Nova Science Publications. Editor: Martin L Weiss, pp 1-60.

Parker D, Bevan S (2007) Modulation of cellular and synaptic variability in the lamprey spinal cord. J Neurophysiol 97: 44-56.

Parker D (2006) Neuroscience and society. International Journal of the Interdisciplinary Social Sciences 1

Parker D (2006) Complexities and uncertainties of neuronal network function. Phil Trans R Soc Lond B 361: 81-99.

Parker D (2005) Pharmacological approaches to functional recovery after spinal injury. Curr Drug Targets CNS Neurol Disord 4: 195-210.

Bevan S, Parker D (2004) Metaplastic facilitation and ultrastructural changes in synaptic properties are associated with long-term modulation of the lamprey locomotor network. J Neurosci 24: 9458-9468.

Parker D (2003) Activity-Dependent Feedforward Inhibition Modulates Synaptic Transmission in a Spinal Locomotor Network. J Neurosci 23: 11085-11093.

Parker D (2003) Variable properties in a single class of excitatory spinal synapse. J Neurosci 23: 3154-3163.

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Cover of the themed issue of the journal Philosophical Transactions of the Royal Society B, Neuronal network analyses: progress, problems, and uncertainties.